Tissue morphogenesis is a highly organized and evolutionarily conserved process controlled by the temporal and tissue-specific activation of signal transduction pathways. An essential step for vertebrate ocular surface morphogenesis is the transient closure and then reopening of eyelid. The temporary closed eyelid ensures a mlcroenvironment favorable for the maturation and development of cornea, lens and retina. Consequently, failure in eyelid developmental closure in mice results in severe ocular disorders, resembling human congenital diseases, such as conjunctiva-corneal dystrophy, ptosis and microophthalmia. The long- term goal of this project is to understand the molecular mechanisms involved in regulating eyelid morphogenesis and to uncover the underlying causes of congenital eye diseases. Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) plays a crucial role in eyelid morphogenesis. Previous studies have shown that MAP3K1 is responsible for the transmission of morphogenetic activin B signals to Jun N-terminal kinases (JNKs), which in turn phosphorylates transcription factor c-Jun to regulate gene expression events involved in eyelid closure. MAP3K1 ablation in mice results in defective embryonic eyelid closure and an eye open at birth (EOB) phenotype. MAP3K1 is found highly expressed in the leading edge of the eyelid epithelium just prior to the onset of eyelid closure;hence its expression must be controlled by specific developmental signal in a cell type-specific manner. My working hypothesis is that activation of Map3k1 gene promoter and expression serves as a critical determinant factor for embryonic eyelid closure. I propose to use molecular, cellular and genetic approaches to identify the morpohgenetic signals, transcriptional and epigenetic mechanisms involved in the regulation of MAP3K1 expression. Results from this work will establish the mechanistic architecture by which physiological/environemtnal factors regulate MAP3K1 expression thereby affecting eyelid morphogenesis. The in depth molecular understanding of ocular surface morphogenesis and eyelid development is an area under-investigated, but potentially important for clinical diagnosis of congenital disease and development of treatment strategies. Human eye problems at birth are difficult to diagnose and their causes are poorly understood. Human eye formation and development undergoes similar processes as mice. Using the well-established experimental systems in mice, I will learn how human eyelid development is regulated and identify the genetic and environmental factors important for governing eye formation. My study will uncover the causes of some eye diseases at birth and lead to the development of new diagnostic tools and treatments for. prevention and cure.